The Staphylococci make up a medically important genera of microbes. They are known to produce two types of disease, invasive and toxigenic. Invasive infections are characterized generally by abscess formation effecting both skin surfaces and deep tissues. Staphlococcus aureus is the second leading cause of bacteremia in cancer patients. Osteomyelitis, septic arthritis, septic thrombophlebitis and acute bacterial endocarditis are also relatively common. There are at least three clinical conditions resulting from the toxigenic properties of Staphylococci. The manifestation of these diseases result from the actions of exotoxins as opposed to tissue invasion and bacteremia. These conditions include: Staphylococcal food poisoning, scalded skin syndrome and toxic shock syndrome.
This invention provides novel spo-rel, which can be used, among other things, for screening for pharmaceutical compounds to treat Staphylococcal infections. In E. coli relA and spoT proteins are involved in the stringent response to nutrient limitation and regulate the accumulation of (p)ppGpp which is involved in the regulation of gene expression and other cellular processes (see Cashel, M. et al. The Stringent Response. In F. C. Neidhardt et al. (eds) Escherichia coli and Salmonella: cellular and molecular biology, 2n edition, ASM Press, Washington, D.C., 1996). The spoT protein is capable of both the synthesis and degradation of (p)ppGpp while the relA protein is capable of (p)ppGpp synthesis only. The spoT and relA proteins are homologous being 55.6% similar and 31.9% identical (Metzger et al., J. Biol. Chem. 264:9122-9125, 1989).
The genetic organization of the streptokinase region of the Streptococcus equisimilis H46A chromosome has been defined including the sequence of a full length ORF of a relA/spoT homolog, desingated ret (Mechold, U. et al. Mol. Gen. Genet. 241:129-140, 1993). Functional analysis of the rel gene from Streptococcus equisimilis indicates that the encoded protein is similar to E. coli spoT in that it catalzyes both the synthesis and degradation of (p)ppGpp (Mechold, U., et al., J. Bacteriol. 178:1401-1411, 1996).
Clearly, there is a need for factors, such as spo-rel of the invention, that may be used to screen compounds for antibiotic activity and which may also be used to determine their roles in pathogenesis of infection, dysfunction and disease. There is a need, therefore, for identification and characterization of such factors which can play a role in preventing, ameliorating or correcting infections, dysfunctions or diseases.
The polypeptide of the present invention has amino acid sequence homology to known guanosine 3', 5'-bis(diphosphate) synthetase/hydrolase protein.